Process for the production of unsaturated 17 α-cyanomethyl-17 β-h

ABSTRACT

The unsaturated 17α-cyanomethyl-17β-hydroxy steroids of the formula I, ##STR1## in which R 1  =Me, Eth; R 2  =H, Me; R 3  =H, OH, an acetoxy or alkoxy group; R 4  =H, R 5  =OH, an acetoxy, alkoxy group of R 4  and R 5  together represent a keto- or ketal group and double bonds are contained in the basic structure of the steroid, particularly between the 15 and 16 position in the steroid ring, from unsaturated 17-ketosteroids of the general formula II as described herein with the aforementioned meanings of R 1  to R 5  by reacting the unsaturated 17-ketosteroids with LiCH 2  CN and subsequently hydrolyzing. 
     The compounds of formula I are pharmacologically interesting steroid compounds or also intermediate products for the synthesis of highly-effective steroid products which can be used in human and veterinary medicine for the treatment of endocrine disorders and for reproductive control based on their specific hormonal/anti-hormonal actions. 
     The compounds are suitable for the treatment of endometriosis and also in combination with preparations with ethinylestradiol for fertility control.

The invention concerns unsaturated 17α-cyanomethyl-17β-hydroxy steroids,pharmaceutical preparations containing the latter, as well a a processfor their production.

Unsaturated 17α-cyanomethyl-17β-hydroxy steroid derivatives are steroidcompounds of pharmacological interest or also intermediate products forsynthesizing pharmacologically highly-effective steroid products, e.g.17α-cyanomethyl-17β-hydroxy-13-alkyl-4,9-gonadiene-3-one such as"Dienogest" oralso17α-cyanomethyl-17β-hydroxy-13-alkyl-4,9,11-gonatriene-3-onederivatives which can be used in human and veterinary medicine in anadvantageous manner for the treatment of endocrine disorders and forreproductive control based on their specific hormonal or anti-hormonalactions. A particular advantage in its application is the goodcompatibility of the compounds, which also produce hardly any unwantedside effects in increased dosages and also represent a desirableenrichment of the range of steroid ingredients of pharmacologicalinterest in comparison to the known 17α-ethinyl-17β-hydroxy steroids.

The introduction of an additional double bond in these17α-cyanomethyl-17β-hydroxy steroids in the C₁₅ /C₁₆ position of thebasic structure of the steroid leads to a significant increase ineffectiveness. A series of these new derivatives show particularlyfavorable dissociations of characteristic partial effectiveness.

According to the invention, the new unsaturated15-dehydro-17α-cyanomethyl-17β-hydroxy steroids of the invention have aring structure as shown in formula I below: ##STR2## wherein R₁ ismethyl or ethyl;

R₂ is selected from the group consisting of hydrogen and methyl;

R₃ is selected from the group consisting of hydrogen, hydroxy, actoxyand alkoxy having 1 to 6 carbon atoms, or

R₄ is hydrogen and R₅ is selected from the group consisting of hydroxy,acetoxy and alkoxy having 1 to 6 carbon atoms, or

R₄ and R₅ are both methoxy or both ethoxy, or

R₄ and R₅, together, represent a keto group or a ketal group selectedfrom the group consisting of --O--CH₂ --CH--O--; --O--CH₂ --C(CH₃)₂--CH₂ --O--; and --OCH(CH₃)--CH₂ --CH(CH₃)--O--;

The new steroids of formula (I) also have at least one other double bondin the ring structure between the 1 and 2 positions, the 2 and 3positions, the 3 and 4 positions, the 4 and 5 positions, the 5 and 6positions, the 5 and 10 positions, the 9 and 10 positions and the 9 and11 positions, the 1,2,3,-4,5,6,9,10 and 11 positions being shown informula I above, with the proviso that R₂ cannot be methyl, when thereis a double bond between the 5 and 10 positions or the 9 and 10positions.

Dosages up to a maximum of 2 mg of active ingredient per day areadvantageous in the application of these new compounds for controllingfertility. These new compounds are administered in combination withestrogen-active steroids such as ethinyl estradiol in the knownpharmaceutical preparation forms as tablets or capsules.

Another area of use of the new active ingredients is the treatment ofspecial diseases, e.g. the treatment of endometriosis. The dosage is upto 2 mg per day over a period if 4 to 6 months in this case also. Theselow dosages show the superiority of the new compounds particularlyclearly while, according to the conventional treatment of theseindications with danazol, the dosage is 400 to 800 mg of danazol daily.

The synthesis of 17α-cyanomethyl-17β-hydroxy steroids has been describedin a series of patents. According to the latter, 17-ketosteroids areconverted in a multiple-step synthesis into thesteroid-17β-spiro-1',2'-oxirane which is then converted with alkalicyanide into 17α-cyanomethyl-17β-hydroxy steroid derivatives. Accordingto K. Ponsold, et al., DD-PS 132 497,3-methoxy-13-alkylgona-2,5(10)-diene-17β-spiro-1',2'-oxiran (producedaccording to DD-PS 80 023) is converted into17α-cyanomethyl-17β-hydroxy-13-alkylgon-5(10)-en-3-one by reacting withalkali cyanide and subsequent enol-ether hydrolysis. An improvement ofthis synthesis was described by K. Ponsold, et al. in DD-WP 160 418,according to which the unstable starting material of the aforementionedprocess (DD-WP 132 497) is replaced by3,3-dimethoxy-13-alkylgon-5(10)-en-3-one which is then converted in thesame manner with trimethylsulfonium iodide, alkali cyanide andsubsequent ketal cleavage into the17α-cyanomethyl-17β-hydroxy-13-alkylgon-5(10)-en-3-one.

Although the individual steps of this synthesis have high yields, theoverall efficiency is burdened by the use of expensive reagents and thehigh cost of labor brought about by the costly intermediate isolations.

The chief disadvantage of this process, however, consists in the highenvironmental loading involved in this synthesis caused by the use of

trimethylsulfonium iodide, which requires that the waste gas and wastewater be disposed of,

alkali cyanide, a poison of Section 1 of the regulations concerningpoison, which places special demands on processing on a technical scaleand requires special disposal of the waste gas ad waste water.

EP 231 671 of Jun. 19, 1986, E. Nitta, et al., describes the synthesisof 17α-cyanomethyl-17β-hydroxy-13-alkylgona-4,9,11-triene-3-onederivative from the corresponding 17-ketosteroids accompanied by the useof the reaction sequence described by K. Ponsold et al.. (DD-WP 160418): --17-ketosteroid→17β-spiro-1',2'-oxiran→17β-cyanomethyl-17β-hydroxy steroid derivatives. Although new compoundsof the 17α-cyanomethyl-17β-hydroxy steroid type were described by thispatent, no improvements of the original synthesis path could bedisclosed, i.e. the aforementioned defects of the high cost of labor andthe high environmental loading also exist in this process. Thecontinuous additional high costs for the disposal of waste products,waste water and waste gas with sulfur compounds and cyanide in thetechnical implementation of this synthesis are added to theaforementioned high costs for carrying out this synthesis, addingsubstantial additional encumbrances to the efficiency of the overallprocess.

The aim of the invention is the synthesis of new pharmacologicallyhighly-effective 17α-cyanomethyl compounds which have a significantincrease in effect or additionally improved dissociation of thecharacteristic partial effects compared with the known17α-cyanomethyl-17β-hydroxy steroid derivatives and can therefore beused more advantageously for the treatment of endocrine disorders andfor reproduction control in human and veterinary medicine due to theirimproved specific effects.

It is also the aim of the invention to develop synthesis methods for theproduction of these new highly-effective 17α-cyanomethyl derivativesrequiring the lowest possible labor costs and preventing environmentalloading to the greatest extent.

The invention has the object of synthesizing new pharmacologicallyhighly-effective 17α-cyanomethyl-17β-hydroxy steroid derivatives andproviding a process according to which the aimed for products can bemade accessible in a technically simple and economically favorablemanner and the cost for secondary processes, particularly waste productselimination/disposal of waste water and waste gas can be minimized asfar as possible.

This object is met, according to the invention, in that unsaturated17-ketosteroids of the formula II, in which the radicals

R₁ =Me, Eth

R₂ =Me, H, R₂ is omitted when there is a doublebond at C₁₀

R₃ =H, OH, acetoxy with 1 to 6 carbon atoms,

R₄ =H

R₅ =OH, acetoxy, alkoxy groups with 1 to 6 carbon atoms, or

R₄ and R₅, together, can represent a keto or ketal group, where (CH₃O)₂, (CH₃ CH₂ O)₂, --O--CH₂ --CH₂ --O--; --O--CH₂ --(Me)C(Me) --CH₂--O--; --O--CH(Me)--CH₂ --(Me)CH--O-- can stand for the ketal group andthere can be double bonds in the basic structure of the steroid moleculein positions C₁ ═C₂, C₂ ═C₃, C₃ ═C₄ ; C₄ ═C₅ ; C₅ ═C₆ ; C₅ ═C₁₀ ; C₉═C₁₀ ; C₉ ═C₁₁ and C₁₅ ═C₁₆, are converted in a single-vessel process ininert organic solvents at low temperatures with LiCH₂ CN which isprepared in situ from CH₃ CN by reacting with lithium alkyls or lithiumdialkylamides (alkyl=C₁ to C₆). The reaction products are worked up withwater. The new steroid compounds of the general formula I in which theradicals R₁ to R₅ have the aforementioned designation and there can bedouble bonds in the aforementioned positions of the basic ring structureof the steroid, are isolated or obtained by direct acid hydrolysis.

The in-situ metallization of the acetonitrile with lithium alkyls orlithium dialkylamides to form LiCH₂ CN and its subsequent reaction in asingle-vessel process with unsaturated 17-ketosteroids to form theunsaturated 17α-cyanomethyl-17β-hydroxy steroids is effected in inertorganic solvents such as aliphatic or aromatic hydrocarbons, preferablypentane, hexane, heptane, benzene, toluene etc. Ethers, preferablediethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, anisole,methyl t-butyl ether dimethoxyethane, diethoxyethane etc. or also intertiary amines, e.g. triethylamine, diisopropylethylamine, pyridine,tetraalkyl ethylenediamine etc. or these solvents can also be used asmixtures.

According to the process according to the invention, 1 to 5 moles ofacetonitrile and 1 to 5 moles of lithium alkyl or lithium dialkylamideare used per mole of unsaturated 17-ketosteroid in such a way that theacetonitrile is converted in situ at low temperatures with the utilizedlithium derivatives into the LiCH₂ CN and the latter is reacted with theunsaturated 17-ketosteroid to formunsaturated17α-cyanomethyl-17β-hydroxy steroid.

This process also includes the in-situ preparation of the LiCH₂ CN inthe presence of the unsaturated 17-ketosteroid and the secondaryreaction with the unsaturated 17-ketosteroid to formthe unsaturated17α-cyanomethyl-17β-hydroxy derivative can run its course virtuallysimultaneously.

This process also consists in that the reactions of the alkyl lithiumwith the acetonitrile can also be carried out in the presence of lithiumhalides, i.e. in that the separation of the Li-Hal prior to further useof the alkyl lithium is not required and the presence of lithium halidedoes not disturb the implementation of the subsequent reactions. Thesereactions are advantageously carried out at low temperatures, i.e. intemperature ranges under +/- 0 degrees C., at which the reaction of theLiCH₂ CN with acetonitrile to form β-ketopropionitrile ##STR3## issuppressed extensively or completely. The temperature ranges arepreferably -20° C. to -90° C. The reaction mixtures can be worked up bythe addition of water. The reaction products can be isolated whileobtaining protective groups such as ketals or enol ethers etc. Theseaqueous preparations are advantageously effected at temperatures ≦-10°C. in pH ranges ≧ pH 6. The pH can also be adjusted by the additions ofsalts such as NH₄ Cl, NH₄ OAc, NaH₂ pO₄ or also acids.

However, the preparation can also be carried out in such a way that thedissolution of the reaction mixtures, i.e. the destruction of thesurplus lithium organyl, is effected with the addition of water andacids or diluted acids and at pH ranges ≦ pH 6 and, in so doing,protective groupings such as ketals, enol ethers etc. which are possiblypresent in the molecule are split. In this case, inorganic acids, e.g.HCl, H₃ PO₄ etc. or also organic acids, e.g. acetic acid, oxalic acid,p-toluenesulfonic acid etc. are used as acids.

The preparation can proceed generally in such a way that thedecomposition of the surplus Li-organyl can be begun at low temperaturesand the acid hydrolysis can then be continued at temperature of up to50° C. The isolation of the reaction products can be effected byextraction or precipitation, but it is advantageous to distill off thesolvent mixture from the reaction mixture in a vacuum and to isolate thehighly pure crystals which occur in this process or by addition ofalcohol or ketone.

The following compounds were synthesized with this process:

13-methyl-17α-cyanomethyl-17β-hydroxy-5(10),15-gonadiene-3-one

13-methyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadiene-3-one

13-methyl-17α-cyanomethyl-3,17β-dihydroxy-gona-1,3,5(10),15-tetraene

13-methyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-1,3,5(10),15-tetraene

13-methyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-3,5(10),15-triene

13-methyl-3,3-dialkoxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene

13-methyl-3,3-ethylenedioxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene

13-ethyl-17α-cyanomethyl-17β-hydroxy-5(10),15-gonadiene-3-one

13-ethyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadiene-3-one

13-ethyl-17α-cyanomethyl-3,17β-dihydroxy-gona-1,3,5(10),15-tetraene

13-ethyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-1,3,5(10),15-tetraene

13-ethyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-3,5(10),15-triene

13-ethyl-3,3-dialkoxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene

13-ethyl-3,3-ethylenedioxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene

The use of the new process, the one-step introduction of the cyanomethylgroup into the 17α-position of the steroid molecule, provides thepreconditions for an environmentally sound synthesis which can beimplemented technically. The known environmental loading is preventedwith this new process, since the solvents are extensively recovered, thelithium salt occurring in the preparation can be separated outfavorably, and the residual amounts of acetonitrile contained in thewaste water are biodegradable in diluted solutions (Martinez,"Immobilization, Detoxification and Destruction of Chemicals"[Immobilisation, Entgiftung und Zerstorung von Chemikalien], 1stedition, Verlag Harri Deutsch, Thun-Frankfurt/Main, page 211).

EXAMPLE 1

2-Methoxy-13-ethyl-17α-cyanomethyl-17β-hydroxy-3,5,15-gonatriene

9.5 ml butyllithium solution (1.4.5 mmoles butyllithium) are placed in areaction vessel in inert gas, cooled to temperatures <-60 ° C. and thenmixed with 10.0 ml purified, dry tetrahydrofuran. 0.78 ml acetonitrile(15 mmoles) are added to this solution accompanied by stirring andcooling. A solution of 2g 3-methoxy-13-ethyl-3,5,15-gonatriene-17-one(6.7 moles) is then added in 10 ml tetrahydrofuran in such a way thatthe reaction temperature of -60° C. is not exceeded. After adding thesteroid solution, subsequent reaction is allowed to take place foranother hour, the temperature of the reaction mixture is allowed to riseto approximately -10° C. and 10 ml water is added to it by dropsbeginning at this temperature. The temperature of the reaction mixturecan rise to +10° C. The phases are separated, the organic phase isreduced and the residue is crystallized with methanol.

Yield: 1.8 g=79% of theory

Flame point: 195.2° C. to 197.5° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.90ppm (tr, 3H, J=7 Hz, 18--CH₂ --CH₃); 2.54 ppm (s, 2H, 17α--CH₂ --CN);3.28 ppm (s, 3H, 3--OCH₃); 5.23 ppm (s, 1H, 4-CH); 5.30 ppm (m, 1H,6--CH); 5.74 ppm (dd, 1H, J=6 Hz and 3 Hz, 15--CH); 6.00 ppm (d, 1H, J=6Hz, 16--CH).

EXAMPLE 2

13-Ethyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadiene-3-one

According to the process described in Example 1, 2 g of3-methoxy-13-ethyl-3,5,15-gonatriene-17-one is converted to3-methoxy-13-ethyl-17α-cyanomethyl-17β-hydroxy-3,5,15-gonatriene atreaction temperatures <-35° C. After the subsequent reaction thereaction mixture is mixed with diluted sulfuric acid at temperaturesbeginning at approximately -15° C. The temperature of the reactionmixture can rise to 25° C. After separating the aqueous phase, theorganic phase is reduced in a vacuum and crystallized with the additionof methanol. After crystallization, it is stirred for up to 1 hour andthen cooled to approximately 10° C. and the resultant crystals arefiltered with suction.

¹ H=-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.94ppm (tr, 3H, J=7 Hz, 18--CH₂ --CH₃); 2.55 ppm (s, 17α--CH₂ --CN); 5.78ppm (dd, 1H, J=6 and 3 Hz, 15--CH); 5.89 ppm (s, 1H, 4--CH); 6.03 ppm(d, 1H, J=6 Hz, 16--CH).

EXAMPLE 3

3-Methoxy-17α-cyanomethyl-17β-hydroxy-1,3,5(10),15-estratetraene

27.7 ml butyllithium solution (0.0443 moles) are added to a sulfuratingflask in inert gas and cooled to -60° C. accompanied by stirring. Atthis temperature, 15 ml tetrahydrofuran and 2.5 ml acetonitrile areadded one after the other in such a way that the temperature of thereaction mixture does not exceed --60° C. 5.0 g Δ15-estrone-3-methylether are dissolved and suspended in 20 mltetrahydrofuran and added to the reaction mixture in such a way that thetemperature of the reaction mixture does not exceed -40° C. during theaddition. After adding the steroid mixture, subsequent reaction isallowed to take place at the above-indicated temperature for up to 1hour, the temperature is allowed to rise to -20° C. and the reactionmixture is then dissolved by adding 20 ml water and is adjusted to theneutral point by the addition of diluted sulfuric acid. After the phaseare separated, the organic phase is reduced in a vacuum. The obtainedresidue is crystallized from methanol and isolated.

Yield: 4.5 g

¹ H=NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.97ppm (s, 3H, 18--CH₃); 2.58 ppm (d, 2H, 17α--CH₂ CN); 3.80 ppm (s, 3H,3--OCH₃); 5.82 ppm (dd, 1H, J=6 and 3 Hz, 15--CH); 6.16 ppm (d, 1H, J=6Hz, 16--CH); 6.68 ppm (m, 1H, 4--CH); 6.78 ppm (dd, 1H, 2--CH); 7.21 ppm(d, 1H, 1--CH).

EXAMPLE 4

13-Ethyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadiene-3-one

According to the process described in Example 1, 4.0 g3,3-(propylene-1,3-dioxy)-13-ethyl-5, 15-gonadiene-17-one are convertedwith a mixture of butyllithium, tetrahydrofuran and acetonitrile attemperatures <-35° C. After acid hydrolysis and extraction with CHCl₃,2.9 g of product crystals are isolated.

EXAMPLE 5

3,3-Dimethoxy-17α-cyanomethyl-17β-hydroxy-5(10)-estren

42 ml butyllithium solution (68mmoles butyllithium) are placed in areaction vessel rinsed with inert gas and diluted with 25 ml purified,dry tetrahydrofuran at a temperature <-60° C. 3.5 ml acetonitrile (68mmoles) are then added to the almost clear solution at temperatures<-60° C. accompanied by stirring and cooling. After the acetonitrile hasbeen added, a solution of 5 g 3,3-dimethoxy-5(10)-estren-17-one (23mmoles) in 25 ml tetrahydrofuran is added to the obtained suspension.The addition has been effected in such a way that the reactiontemperature is maintained <-40° C. After a subsequent reaction time of30 min the reaction solution is heated and 20 ml water is added to themixture by drops at a temperature of 0° C. to 10° C. The obtainedtwo-phase system is separated and the organic phase is reduced in avacuum. The raw product is then dissolved in 40 ml chloroform and theorganic phase is washed three times with 20 ml water. After reducingagain, 5.4 g yellow oil (95% of theory) is obtained. DC tests resultedin a uniform product.

EXAMPLE 6

17α-Cyanomethyl-17β-hydroxy-5(10)-estren-3-one

5 g of 3,3-ethylenedioxy-5(10)-estren-17-one is converted to17α-cyanomethyl-3,3-ethylenedioxy-17β-hydroxy-5(10)-estren correspondingto the test implementation mentioned in Example 1. After the subsequentreaction time, it is mixed with diluted H₂ SO₄ and stirred intensivelyfor 30 min at room temperature. After the phases are separated theorganic phase is reduced and the obtained yellow oil is crytallized withthe aid of acetone. 4.55 g (92% of theory) of17α-cyanomethyl-17β-hydroxy-5(10)-estren-3-one are obtained.

Flame point: 175.7° C. to 177.4° C.

¹ H-NMR spectrum: (80 HMz, CDCl₃, 6 against TMS as inner standard) 0.98ppm (s, 3H, 18--CH₃); 2.46 ppm (m, 4H, 1--CH₂, 3--CH₂); 2.63 ppm (m, 2H,17α--CH₂ CN); 2.76 ppm (m, 2H, 4--CH₂).

EXAMPLE 7

17α-Cyanomethyl-17β-hydroxyandrosten-3-one

10 ml butyllithium solution (13mmoles butyllithium) are placed in thereaction vessel with an inert gas flow and cooled. At temperatures <-60°C. the solution is mixed with 10 ml tetrahydrofuran and subsequentlywith 0.75 ml acetonitrile (14 mmoles). A solution of 1.9 g3-methoxy-3,5-androstadiene-17-one (6.3 moles) in 10 ml tetrahydrofuranis added to the obtained suspension in such a way that the reactiontemperature does not exceed -30° C. Further preparation is effected asin Example 1. The obtained product is subsequently converted in themethanol with the addition of acid toform17α-cyanomethyl-17β-hydroxy-4-androsten-3-one. 1.85 g (85% oftheory) crystals are obtained.

Flame point: 278.8° C. to 281.1° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.98ppm (s, 3H, 18--CH₃); 1.25 ppm (s, 5H, 19--CH₃); 2.52 and 2.63 ppm (d,2H, 17α--CH₂ CN); 5.76 ppm (s, 1H, 4--CH)

EXAMPLE 8

17α-Cyanomethyl-3,17β-dihydroxy-5-androsten

20 ml butyllithium is added to a reaction vessel in inert gas, cooled toapproximately -70° C. and mixed with 20 ml tetrahydrofuran. 1.5 mlacetonitrile in 10 ml tetrahydrofuran is added to this solutionaccompanied by stirring and cooling. A solution of 3.6 g androstenolonein 30 ml tetrahydrofuran is hen added in such a way that the reactiontemperature of -60° C. is not exceeded. After the addition of thesteroid solution, a subsequent reaction is effected up to 1 hour, thetemperature is allowed to rise to approximately 10° C. and the mixtureis then added to water accompanied by stirring. The reaction product isextracted with chloroform, the CHCl₃ phases are washed repeatedly withwater and then reduced as far as possible in a vacuum. The residue isthen crystallized from CHCl₃.

Flame point: 214.7° C. to 214.9° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.81ppm (s, 3H, 18--CH₃); 0.99 ppm (s, 3H, 19--CH₃); 2.63 ppm (s, 2H,17α--CH₂ CN)).

EXAMPLE 9

3-Methoxy-17α-cyanomethyl-17-hydroxy-1,3,5(10)-estratriene

13 ml butylllithium (20 mmoles) are cooled to <-60° C. in inert gaswhile stirring and mixed with 15 ml tetrahydrofuran. After adding 1.1 mlacetonitrile (20 mmoles) at a reaction temperature of <-60° C., a whitesuspension is obtained. 2.5 g estrone-3-methylether are suspended andpartially dissolved in 20 ml tetrahydrofuran and added to the reactionsolution in such a way that a temperature of -60° C. is not exceeded.After 30 min of stirring at <-60° C., it is dissolved with 20 ml water.The phases are separated and the organic phase is reduced in a vacuum.The 17α-cyanomethyl-17β-hydroxy-1,3,5(10)-estratriene-3-methylethercrystallizes from a mixture of acetone and water with a yield of 78% oftheory.

Flame point 149.2° C. to 149.9° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.95ppm (s, 3H, 18--CH₃); 2.59 ppm (d, 1H, J=16 Hz, 17α--CH₂ CN); 2.69 ppm(d, 1H, J=16 Hz, 17α--CH₂ CN); 3.80 ppm (s, 3H, 3--OCH₃); 6.68 ppm (m,1H, 4--CH); 6.72 ppm (dd, 1H, J=2 and 9 Hz); 7.22 ppm (d, 1H, J=9 Hz, 1CH).

EXAMPLE 10

3-Methoxy-13-ethyl-17α-cyanomethyl-17β-hydroxy-3,5-gonadiene

10 ml butyllithium solution (0,028 moles butyllithium) are added to areaction vessel in inert gas, cooled to temperatures <-35° C. and thenmixed with 30 ml purified, dry tetrahydrofuran. 1.15 ml aceetonitrile(0,022 moles) are added to this solution accompanied by stirring andcooling. A solution of 3.0 g 3-methoxy-13-ethyl-3,5-gonadiene-17-one(0.01 mole) in 25 ml tetrahydrofuran is then added in such a way thatthe reaction temperature of -30° C. is not exceeded. After adding thesteroid solution, subsequent reaction is carried out for another 30 min,the temperature of the reaction mixture is then allowed to rise toapproximately -10° C. and 50 ml water are added to it by drops at thistemperature. The reaction temperature can rise to +10° C. The obtainedtwo-phase mixture is separated and the organic phase is reduced in avacuum. The obtained residue is absorbed in chloroform, the CHCl₃solution is washed to neutral point with water, dried over Na₂ SO₄, andthen reduced as far as possible in a vacuum.

Yield: 69%

Flame point: 192.7° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 1.04ppm (tr, 3H, J=7 Hz, 18--CH₂ --CH₃); 2.53 ppm (d, 1H, J=16 Hz, 17--CH₂CN); 2,68 ppm (d, 1H, J=16 Hz, 17--CH₂ CN); 3.60 ppm (s, 3H, 3--OCH₃);5.25 ppm (s, 1H, 4--CH); 5.28 ppm (m, 1H, 6--CH)

EXAMPLE 11

13-Methyl-17α-cyanomethyl-17β-hydroxy-4-gonen-3-one

3.0 g 3-methoxy-13-methyl-3,5-gonadiene-17-one are converted in a manneranalogous to that in Example 6.

Yield: 74% of theory

Flame point: 243° to 246° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.84ppm (s, 3H, 18--CH₃); 2.63 ppm (2d, 2H 17α--CH₂ CN); 5.75 ppm (s, 1H,4--CH).

EXAMPLE 12

17α-Cyanomethyl-17β-hydroxy-13-methyl-5(10),9(11)-gonadiene-3-one

36 ml butyllithium solution (1.3 moles/1) are placed in a reactionvessel rinsed with inert gas and diluted with 10 ml tetrahydrofuran at-60° C. 3 ml acetonitrile are then added to this solution accompanied bystirring and cooling in such a way that the temperature of -60° C. isnot exceeded. A solution of 2.5 g13-methyl-3,3-dimethoxy-5(10),9(11)-gonadiene-17-one in 20 mltetrahydrofuran is then added by drops to this reaction mixture in sucha way that the above-indicated temperature range is not exceeded. Afteradding the substance, the reaction mixture is stirred for 30 min, thetemperature is allowed to rise to +-0° C, diluted sulfuric acid is addedto the reaction mixture by drops and the reaction mixture is stirred foranother 30 min at room temperature. The aqueous phase is then separatedoff, reextracted two times with methylene chloride, the unified organicphase is washed free of acid and then reduced in a vacuum. Thedistillation residue is mixed with acetone for crystallization and thecrystalline product is removed by suction after standing overnight.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 0.93ppm (s, 3H, 18--CH₃); 2.56 ppm (m, 6H, 1--CH₂, 2--CH₂, 17α--CH₂ CN);2.90 ppm (m, 2H, 4--CH₂); 5.65 ppm (m, 1H, 11--CH)

EXAMPLE 13

3-Ethyl-17α-cyanomethyl-17β-hydroxy-4,9-gonadiene-3-one

6.5 ml butyllithium solution, 10 ml THF, 1.8 ml acetonitrile are reactedwith 13-ethyl-3,3-ethylenedioxy-5(10),9(11)-gonadiene-17-one attemperatures ≦-30° C. and with subsequent dissolution with 30 ml waterto form13-ethyl-3,3-ethylenedioxy-17α-cyanomethyl-17β-hydroxy-5(10),9(11)-gonadieneaccording to the process described in Example 1. Isolation of theproduct and reaction with concentrated hydrochloric acid in ethanolafter CHCl₃ extraction, reduction and crystallization from ethanol/waterresults in 13--ethyl-17α-cyanomethyl-17β-hydroxy-4,9-gonadiene-3-one.

Yield: 56% of theory

Flame point: 214° C. to 215° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 1.16ppm (tr, 3H, J=7 Hz, 18--CH₂ --CH₃); 2.53 ppm (d, 1H, J=16 Hz, 17--CH₂CN); 2.68 ppm (d, 1H, J=16 Hz, 17--CH₂ CN); 5.78 ppm (s, 1H 4--CH)

EXAMPLE 14

13-Methyl-17α-cyanomethyl-17β-hydroxy-4,9-gonadiene-3-one.

16.5 ml butyllithium solution are placed in a reaction vessel in inertgas, cooled to temperatures <-35° C. and mixed with 15 mltetrahydrofuran. 1.8 ml acetonitrile/10 ml tetrahydrofuran are added tothis solution. A solution of 5 g3,3-(1,3-propylenedioxy)-13-methyl-5(10),9(11) -gonadiene-17-one is thenadded in 30 ml THF and the reaction mixture is kept at a temperature of≦-35° C. for up to one hour, the reaction mixture is then dissolved with40 ml water and the organic phase is isolated. The organic phase isreduced, absorbed in ethanol, mixed with 1 ml concentrated HCl andstirred for 2 hours at room temperature, the solution is reduced and theobtained crystallisate is isolated.

Yield: 4.0 g

Flame point: 208° C. to 211.5° C.

¹ H-NMR spectrum: (80 MHz, CDCl₃, δ against TMS as inner standard) 1.09ppm (s, 3H, 18--CH₃); 2.47 ppm (s, 4H,1 CH₂ and 2 (CH₂); 2.52 ppm (s,1H, J=16.4 Hz, 17--CH₂ CN); 2.63 ppm (s, 1H, J=16.4 Hz, 17--CH₂ CN);5.71 ppm (s, 1, H, 4--CH).

EXAMPLE 15

13-methyl-17α-cyanomethyl-17β-hydroxy-4,9,11-gonatriene-3-one

20 ml n-butyllithium solution (26 mmoles) are placed in a reactionvessel in an inert gas flow and cooled. At temperatures of -40° C. thesolution is mixed with 20 ml methyl-t.-butyl ether and then with 1.5 mlacetonitrile. A solution of 3.8 g of3,3-ethylenedioxy-13-methyl-4,9,11-genatriene-17-one in 20 mlmethyl-t.-butyl ether is added to the obtained suspension in such a waythat the reaction temperature does not exceed -25° C. Continuedpreparation is effected as in Example 1. The obtained product is thenconverted in methanol with the addition of acid at pH 2.5 to13-methyl-17α-cyanomethyl-17β-hydroxy-4,9,11-gonatriene.

Yield: 2.38 g (63.3%)

flame point: 152° C. to 155° C.

EXAMPLE 16

13-Ethyl-17α-cyanomethyl-17β-hydroxy-4,9,11-gonatriene-3-one

1.95 g 3,3-ethylenedioxy-13-ethyl-4,9,11-gonatriene-17-one is convertedto 0.89 13-ethyl-17α-cyanomethyl-17β-hydroxy-4,9,11-gonatriene-3-oneaccording to the process described in Example 15.

Flame point: 193° C. to 195° C.

While the invention has been illustrated and described as embodied in aprocess for production of unsaturated 17α-cyanomethyl-17β-hydroxysteroids, it is not intended to be limited to the details shown, sincevarious modifications and structural changes may be made withoutdeparting in any way from the spirit of the present invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. Unsaturated15-dehydro-17α-cyanomethyl-17β-hydroxy steroids of the formula ##STR4##wherein R₁ is methyl or ethyl;R₂ is selected from the group consistingof hydrogen and methyl; R₃ is selected from the group consisting ofhydrogen, hydroxy, acetoxy and alkoxy having 1 to 6 carbon atoms; R₄ ishydrogen and R₅ is selected from the group consisting of hydroxy,acetoxy and alkoxy having 1 to 6 carbon atoms, or R₄ and R₅ are bothmethoxy or both ethoxy, or R₄ and R₅, together, represent a keto groupor a ketal group selected from the group consisting of --O--Ch₂ --CH₂--O--; --O--CH₂ --C(CH₃)₂ --CH₂ --O-- and --OPCH(CH₃)--CH₂--CH(CH₃)--O--; wherein said steroids of formula (I) also have at leastone other double bond between the 1 and 2 positions, the 2 and 3positions, the 3 and 4 positions, the 4 and 5 positions, the 5 and 6positions, the 5 and 10 positions, the 9 and 10 positions and the 9 and11 positions, said 1,2,3,4,5,6,9,10 and 11 positions being shown in theformula I above; and with the proviso that R₂ cannot be methyl, whensaid at least one other double bond is between the 5 and 10 positions orbetween the 9 and 10 positions.
 2. Asteroid according to claim 1,consisting of13-methyl-17α-cyanomethyl-17β-hydroxy-5(10),15-gonadien-3-one. 3.Asteroid according to claim 1, consisting of13-methyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadien-3-one.
 4. Asteroidaccording to claim 1, consisting of13-methyl-17α-cyanomethyl-3,17β-dihydroxy-gona-1,3,5(10),15-tetraene. 5.Asteroid according to claim 1, consisting of13-methyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-1,3,5(10),15-tetraene.
 6. Asteroid according to claim 1, consisting of13-methYl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-3,5(10)15-triene.7. Asteroid according to claim 1, consisting of13-methyl-3,3-dialkoxy-17α-cyanomethyl-17β-hydroxy-gona -5(10),15-diene,wherein said alkoxy groups have 1 to 6 carbon atoms.
 8. Asteroidaccording to claim 1, consisting of13-methyl-3,3-ethylenedioxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene.9. Asteroid according to claim 1, consisting of13-ethyl-17α-cyanomethyl-17β-hydroxy-5(10),15-gonadien-3-one. 10.Asteroid according to claim 1, consisting of13-ethyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadien-3-one.
 11. Asteroidaccording to claim 1, consisting of13-ethyl-17α-cyanomethyl-3,17β-dihydroxy-gona-1,3,5(10),15tetraene. 12.Asteroid according to claim 1, consisting of13-ethyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-1,3,5(10),15tetraene.
 13. Asteroid according to claim 1, consisting of13-ethyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-3,5(10),15-triene.14. Asteroid according to claim 1, consisting of13-ethyl-3,3-dialkoxy-17α-cyanomethyl-17β-hydroxy-gona -5(10),15-diene.15. Asteroid according to claim 1, consisting of13-ethyl-3,3-ethylenedioxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene.
 16. Unsaturated 15-dehydro-17α-cyanomethyl-17β-hydroxysteroids selected from the group consisting of13-methyl-17α-cyanomethyl-17β-hydroxy-5(10),15-gonadien-3-one,13-methyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadien-3-one,13-methyl-17α-cyanomethyl-3,17β-dihydroxy-gona-1,3,5(10),15-tetraene,13-methyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-1,3,5(10),15-tetraene,13-methyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-3,5(10),15-triene,13-methyl-3,3-dialkoxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene,13-methyl-3,3-ethylenedioxy-17α-cyanomethyl-17β-hydroxy-gona-5(10)-diene,13-ethyl-17α-cyanomethyl-17α-hydroxy-5(10),15-gonadien-3-one,13-ethyl-17α-cyanomethyl-17β-hydroxy-4,15-gonadien-3-one,13-ethyl-17α-cyanomethyl-3,17β-dihydroxy-gona-1,3,5(10),15-tetraene,13-ethyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona,1,3,5(10),15-tetraene,13-ethyl-3-methoxy-17α-cyanomethyl-17β-hydroxy-gona-3,5(10),15-triene,13-ethyl-3,3-dialkoxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene,and13-ethyl-3,3-ethylenedioxy-17α-cyanomethyl-17β-hydroxy-gona-5(10),15-diene.17. Pharmaceutical composition comprising a therapeutically effectiveamount of an unsaturated steroid as defined in claim 1 in apharmaceutically acceptable carrier.
 18. Pharmaceutical compositioncomprising a therapeutically effective amount of an unsaturated steroidas defined in claim 16 in a pharmaceutically acceptable carrier. 19.Pharmaceutical composition as defined in claim 18, further comprisingethinyl estradiol.
 20. Process for making an unsaturated15-dehydro-17α-cyanomethyl-17β-hydroxy steroid of the formula I:##STR5## wherein R₁ is methyl or ethyl;R₂ is selected from the groupconsisting of hydrogen and methyl; R₃ is selected from the groupconsisting of hydrogen, hydroxy, acetoxy and alkoxy having 1 to 6 carbonatoms; R₄ is hydrogen and R₅ is selected from the group consisting ofhydroxy, acetoxy and alkoxy having 1 to 6 carbon atoms, or R₄ and R₅ areboth methoxy or both ethoxy, or R₄ and R₅, together, represent a ketogroup or a ketal group selected from the group consisting of --O--CH₂--CH₂ --O--; --O--CH₂ --C(CH₃)₂ --CH₂ --O--; and--OCH(CH₃)--CH2--CH(CH₃)--O--;wherein said steroids of formula (I) alsohave at least one other double bond between the 1 and 2 positions, the 2and 3 positions, the 3 and 4 positions, the 4 and 5 positions, the 5 and6 positions, the 5 and 10 positions, the 9 and 10 positions and the 9and 11 positions, said 1,2,3,4,5,6,9,10 and 11 positions being shown informula I above; and with the proviso that R₂ cannot be methyl, whensaid at least one other double bond is between 5 and 10 positions or the9 and 10 positions; comprising the steps of: a) forming Li--CH₂ CN in aninert organic solvent by reacting acetonitrile with a lithium compoundselected from the group consisting of lithium alkyl compounds havingalkyl groups containing from one to six carbon atoms and lithium dialkylcompounds having alkyl groups containing from one to six carbon atoms inthe inert organic solvent; b) after step a), reacting an unsaturated17-ketosteroid of the formula II: ##STR6## with the Li--CH₂ CN containedin the inert organic solvent to form a reaction mixture, said R₁, R₂,R₃, R₄ and R₅ being the same as in said formula I; and c) after step b),hydrolyzing the reaction mixture to obtain the unsaturated steroid offormula (I).
 21. Process as defined in claim 20, wherein the inertorganic solvent is selected from the group consisting of aromatichydrocarbons, aliphatic hydrocarbons, ethers, tertiary amines andmixtures thereof.
 22. Process as defined in claim 21, wherein thetertiary amines are selected from the group consisting of triethylamine,diisopropylamine, pyridine and tetraalkyl ethylenediamine.
 23. Processas defined in claim 21, wherein the ethers are selected from the groupconsisting of diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane, anisole, dimethoxyethane, diethoxyethane and methyl-t-butylether.
 24. Process as defined in claim 21, wherein the aromatichydrocarbons are selected from the group consisting of benzene andtoluene.
 25. Process as defined in claim 21, wherein the aliphatichydrocarbons are selected from the group consisting of pentane, hexaneand heptane.
 26. Process as defined in claim 20, wherein during thereacting step b) one mole of the unsaturated 17-ketosteroid of theformula II is added to the inert organic solvent containing the Li--CH₂CN for each 1 to 5 moles of the acetonitrile used to form the Li--CH₂CN.
 27. Process as defined in claim 20, wherein the reacting step b) isperformed at a reaction temperature of -20° C. to -90 ° C.
 28. Processas defined in claim 20, wherein the hydrolyzing step c) is performed byadding water to the reaction mixture at hydrolysis temperatures of lessthan -10° C. and at pH values greater than
 6. 29. Process as defined inclaim 28, further comprising adjusting the pH values by addition of amember selected from the group consisting of salts and acids. 30.Process as defined in claim 29, wherein the salt is selected from thegroup consisting of ammonium acetate and ammonium phosphate.
 31. Processas defined in claim 20, wherein the hydrolyzing step c) is performed, atleast in part, by adding an aqueous acid solution to the reactionmixture to form the unsaturated steroid of formula (I) above, andwherein the hydrolyzing step c) is performed at a pH value of less than6 and at hydrolysis temperatures of up to 50° C.
 32. Process as definedin claim 31, further comprising adjusting the pH values by addition of amember selected from the group consisting of salts and acids. 33.Process as defined in claim 32, wherein said acids are selected from thegroup consisting of HCl, H₃ PO₄, H₂ SO₄, HClO₄, acetic acid, oxalic acidand toluene sulfonic acid.